This application addresses broad Challenge Area (06): Enabling Technologies and specific Challenge Topic, 06-DC-103: Understanding the Neural Mechanisms Responsible for Tinnitus. The proposed work will investigate a completely new brain mechanism for tinnitus directly in people. This mechanism - abnormal coordination, or coupling, between brain centers - is manifested strikingly in our preliminary analyses of functional magnetic resonance (fMRI) data: Tinnitus subjects, but not non-tinnitus controls, demonstrate an abnormal coupling of activity between non-primary auditory cortex and frontal areas known to mediate emotions. This abnormal coupling is strongly suggestive of one of the most clinically perplexing aspects of the tinnitus condition, the "vicious cycle" whereby the tinnitus percept causes distress and distress exacerbates the percept. The possibility that aberrant coupling between brain areas may be the tie that binds tinnitus percept and affect is, by itself, strong motivation for the present proposal. The possibility that our initial observations are only the tip of the iceberg is all the more reason to examine a brain mechanism that may prove to be a crucial aspect of the physiology of tinnitus. Here, we propose behavioral, fMRI, magneto- and electro-encephalographic (MEG, EEG) measurements in tinnitus subjects and non-tinnitus controls to test for, quantify, and establish the behavioral significance of aberrant coordination between brain centers in tinnitus subjects. We expect this work will fundamentally change how the field conceptualizes the brain mechanisms of tinnitus. It promises to also bring us closer to the day when every one of the millions of Americans plagued by tinnitus can enter a clinic and walk away cured. PUBLIC HEALTH RELEVANCE: This proposal investigates a novel abnormality of brain function that may underlie the most clinically significant aspect of tinnitus, the "vicious cycle": tinnitus causes distress;distress causes tinnitus. The nature of the abnormality - to be studied directly in people - is an unusually strong coupling of activity between brain centers such as those processing sound and emotions. If our work shows that this abnormal coupling is indeed operative in tinnitus patients, there are existing treatments that may be able to reverse it and thereby provide relief from a condition that is all too often debilitating.